Therapeutic drugs often require monitoring after they are administered. In many instances, the effectiveness of the drug is directly related to the concentration of the drug in the bloodstream. In such cases, the rate at which the desired blood level is achieved or exceeded will depend upon the nature of the drug, the manner of administration, the dosage, as well of the rate of metabolism. The rate at which a drug will enter the blood stream when administered other than intravenously and the rate at which the drug is metabolized varies widely with individuals. Furthermore, the level of effectiveness will also vary widely with individuals.
It is therefore desirable when administering drugs to ascertain the individual's level of effectiveness, the rate at which this level is achieved at a particular dosage and the time for which the level is maintained. In this manner, the amount of drug which is administered can then be carefully monitored to maintain the desired level. In this way, effectiveness can be assured and side effects minimized.
In order to monitor a drug in a physiological fluid, it is necessary to have sensitive tests which enable the rapid determination of the drug as distinct from any ineffectual metabolites. Thus, the test must clearly distinguish between the drug of interest and compounds of very similar structure. In competitive protein binding assays, antibodies are employed which are prepared by means of antigenic conjugates of derivatives of the drug of interest. In order for the antibodies to be effective, they must be produced in high titer, have a strong binding constant to the drug of interest, and weakly bind to have little affinity towards compounds of similar structure.
In such assays, a reagent typically provides a measurable signal related to the amount of drug present in the assay medium. Where antibodies are involved, the reagent must effectively compete with the drug for antibody binding in a reproducible manner and provide for significant changes in the signal with small changes in the drug concentration, over the concentration range of interest.
Other considerations for a reagent are that it is not affected by materials present in the unknown sample to be assayed or any interfering materials may be removed, an easily determinable signal is obtained, the reagent is stable under the assay condition and has a good storage life and the reagent is readily recognizable by the antibodies for the drug.
Lidocaine [Merck Index, 13th ed., p. 982 (1997)] was originally developed as a local anesthetic, but also possesses antiarrhythmic properties, particularly against ventricular arrhythmias. It is widely used in the treatment of post-myocardial infarction patients where it is administered by bolus injection of 1 to 2 milligrams per kilogram, followed by constant infusion at a dose level of 20 to 50 micrograms per kilogram per minute. The toxic side effects hypotension, CNS depression, and convulsions appear to be avoidable if the blood levels do not exceed 5 micrograms per milliliter (ml). On long term constant infusions, 24 to 36 hours may be required to reach a steady state. Patients receiving such therapy need to be observed carefully and continuously for signs of lidocaine toxicity. Lidocaine and possibly lidocaine metabolite blood levels may have to be determined in order to treat arrhythmias effectively and fully understand the toxicity of the drug in a given patient.
The preparation of antibodies to lidocaine and its analogs for use in immunoassays has been accomplished in the prior art by forming a particular immunogen conjugate of the drug and a conventional immunogenic carrier material and injecting such immunogen into the bloodstream of an appropriate host animal to stimulate antibody production. U.S. Pat. No. 4,069,105 describes such immunogen conjugates wherein the drug is coupled to the carrier through an imine linkage attached to one of the three unsubstituted positions on the lidocaine phenyl group. U.S. Pat. No. 4,650,771 describes derivatives wherein the drug is linked to a carrier through an aromatic methyl substituent.
While some of these prior art approaches have been effective, there continues to be a need for improvements in precise and sensitive monitoring of lidocaine.